The research project is concerned with the action of drugs and hormones on metabolism. Experiments will be done with the isolated rat heart and with rat diaphragm in vitro. The action of epinephrine on heart contraction and metabolism is markedly influenced by the ionic composition of the perfusion medium. Lithium and magnesium ions in particular depress the positive inotropic effect of epinephrine and also inhibit the usual stimulation of glycogenolysis seen after epinephrine administration. The inhibition of glycogen breakdown produced by magnesium can be overcome by increasing the concentration of calcium. Experiments are planned to elucidate the mechanisms of these metabolic effects of ions on cardiac metabolism. In the isolated diaphragm lithium ions cause a marked increase in glucose utilization and glycogen synthesis but, in contrast to insulin does not stimulate the production of lactate. Experiments are planned to study the effects of lithium and other cations on several aspects of glucose metabolism in the diaphragm including the activity of glycogen synthase. Since calcium uptake and release by mitochondria may play an important role in the regulation of cell metabolism and function we are also continuing our studies in this field.